Hepatitis B virus (HBV) is a small, partially double-stranded DNA virus that causes acute and chronic hepatitis. An estimated 400 million people are chronically infected worldwide, many suffering early death due to liver failure and primary liver cancer (HCC). The chance of clearing HBV infection is age dependent: approximately 90% of neonatal infections become chronic, whereas at least 90% of adult infections are cleared spontaneously. It is generally accepted that a broad and diverse adaptive immune response is important in clearing acute HBV infection. However, why an individual generates, or fails to generate, a favorable response[unreadable]and why this capability varies with age[unreadable]is unknown. The study of HBV immunopathogenesis has been limited because the virus only infects outbred species whose immune systems are difficult to examine, and does not infect mice, the species in which most of the tools to study immunology have been developed. To address this, we have developed the first experimental system to address mechanistic differences in immune responses to very early HBV infection in young and adult humans. This experimental system has produced data that has led to new hypotheses based on experimentation rather than speculation. Prior to these data, the current paradigm posits that [unreadable]immune system immaturity[unreadable], and [unreadable]neonatal tolerance[unreadable] to HBV underpins the greatly increased viral persistence in the young, but this has not been mechanistically explained or definitively validated. Our data suggest that immaturity of the immune priming environment of effector cells in the livers of newborns and young children contributes significantly to the generation of immune responses to HBV that do not differentiate and expand to allow viral control. Our proposal seeks to begin to mechanistically understand the cells and signals that are immature, or are effected by this immaturity. Furthermore, the use of the model outlined in this proposal is likely to provide concepts that broadly impact the understanding of age-dependent immune responses in specific immunologic niches, and concepts that broadly impact our understanding of immunity to hepatotrophic pathogens.